Preliminary models of spheroidal HDL particles through molecular dynamics

In vivo high density lipoproteins (HDL) originate as discoidal prebeta-migrating complexes of the apolipoprotein (apo) A-I and phospholipids which are either secreted from the liver and intestine or are formed extracellularly by the interaction of lipid poor apoA-I with small amounts of phospholipids. These prebeta HDL complexes of apoA-I and phospholipids are highly effective acceptors of unesterified cholesterol (UC) from cell membranes; the accumulation of UC converts them into larger discoidal particles. These latter particles are excellent substrates for the enzyme Lecithin Cholesterol Acyl Transferase (LCAT), which catalyses the transfer of an acyl group from phosphatidylcholine (PC) to cholesterol, generating cholesteryl ester (CE) and lyso-PC. The transition from discoidal to spheroidal HDL (the form of circulating HDL) is driven by phase separation of CE molecules to create a hydrophobic core in the middle of the lipid bilayer. To investigate the conformation of apoA-I in spheroidal HDL particles, we performed all-atom and coarse-grained (CG) molecular dynamics (MD) simulations on a starting model HDL particle produced by a methodology involving incremental removal of palmitoyloleoylphosphatidylcholine (POPC) from a particle with 160 POPC and a belt of two antiparallel amphipathic helical lipid-associating domains of apoA-I. The initial particle, a previously 1 ns MD simulated and a delta40 apoA-I double belt both surrounding a saddle-shaped POPC bilayer with 80 lipid molecules, was subjected to removal of 24 POPC molecules from the center, followed by the insertion of a cluster of 16 cholesteryl oleate molecules (CO). The goal was simulation of spheroidal HDL particle by creating a CO hydrophobic core between the monolayers of the POPC bilayer. In both atomistic and CG MD simulations at 310K the starting model assumes a spheroidal shape. This work was supported by a National Institute of Health grant.